Gluten-Sensitive Diarrhea Without Evidente of Celiac Disease

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GASTROENTEROLOGY 79:801-806. 1980

Gluten-Sensitive Diarrhea Without Evidente of Celiac Disease



The Nutritional and lntestinal Unit, The Genera1 Hospital, Birmingham and The Regional Immunology Laboratory, East Birmingham Hospital, Birmingham, England

Eight adult female patients suffering from abdomi- na1 pain and chronic diarrhea which was often inca- pacitating and frequently nocturnal, had dramatic relief on a gluten-free diet and return of symptoms after gluten challenge. Previous nonspecific mea- sures and a milk-free diet were ineffective. Multiple jejunal biopsies showed minor, but significant changes in celhdarity which returned to normal on the gluten-free diet. Apart from a slight increase in jejunal cellularity, no immunological abnormalities were found after gluten challenge. Steatorrhea or other biochemical defects, common in ceiiac disease, were not found. It was concluded that these patients had a gluten-sensitive diarrhea, but had no evidente of celiac disease.

Celiac disease is usually diagnosed by demonstra- tion of a “flat” jejunal mucosal appearance which improves morphologically on gluten withdrawal from the dieP or which is associated with a “dra- matic clinical response” to such dietary treatment.3 It has also been called gluten-sensitive enteropathy.

The purpose of this paper is to report a group of pa- tients with chronic diarrhea, but with only minor je- junal histologie abnormalities, who are sensitive to gluten and do not appear to have celiac disease.

Clinical Material

During a 4-yr period, 17 patients (15 women and 2 men) who suffered from chronic diarrhea, had received no

Received November 21,1977. Accepted July 11,198O.

Address requests for reprints to: Dr. W. T. Cooke, The Genera1 Hospital, Birmingham B4 6NH, England.

B. T. Cooper and R. Ferguson were in receipt of a Grant from the Centra1 Birmingham Health District Trust Fund.

We are grateful to Dr. Anne Ferguson and Miss L. Henderson of the Western Genera1 Hospital, Edinburgh, Scotland, for testing sera for antigluten antibodies, and to Mrs. Pauline Mackintosh of the Regional Blood Transfusion Centre, Birmingham, for deter- mining the HL-A antigens.

0 1980 by the American Gastroenterological Association 0016-5085/80/110801-06$02.25

definitive diagnosis, or effective treatment despite exten- sive investigation. None had any history of celiac disease in childhood, or had relatives with celiac disease, or symp- toms suggestive of this disorder. None suffered from any atopic complaint, or skin rash resembling dermatitis her- petiformis. Al1 were of English parentage, born in England and had lived al1 their lives in England. After withdrawal of gluten from the diet, 9 showed dramatic clinical im- provement (responders), and 8 showed no significant clini- cal response or morphologic change in their jejunal biopsy (nonresponders). The responders were al1 women aged 24- 47 yr (mean 34 yr) and are the main consideration of this paper.

Presenting Symptoms and Signs (Table 1) Duration of symptoms before presentation ranged from 7 mo to 20 yr (mean 5 yr). Al1 patients had severe persistent chronic diarrhea without any intervening con- stipation. Defecation tended to be explosive, the stools while often watery and offensive, were of normal color and never contained blood or mucus. Diarrhea was suffi- ciently incapacitating in 2 patients to be a social handicap, while 7 patients were frequently disturbed at night. Al1 pa- tients complained of centra1 abdominal, colicky pain eased by defecation. Other prominent symptoms were malaise, abdominal distension, and rumbling. Two patients com- plained of nausea and had persistent anorexia. Al1 were of average height. Weight loss of up to 9.5 kg since the onset of diarrhea was a feature in 8 patients. Recurrent ulcer- ation of the mouth occurred in 3 patients, while 5 had macroglossia and 2 had mild finger clubbing. None were chnically anemie, or had any peripheral edema, lymphad- enopathy, petechiae, skin rashes, hepatosplenomegaly, or abnormal abdominal signs. Sigmoidoscopy was normal in al1 patients.

Laboratory Investigations

Laboratory investigations were within normal range (Table 2) in al1 patients except for 3 with low-serum folie acid values, 1 with raised IgA and IgG serum levels (subsequently developing rheumatoid arthritis), and 1 with low-serum IgA, respectively. None had raised serum IgE levels. Only 3 patients had the HL-A B8 phenotype.


Tabje 2. Clinical Features at Presentation Length of

Age at symptoms

presen- to presen- Diarrhea

tation tation times/ Night Abdominal Abdominal Poor Weight Aphthous Macro- Finger No. (yr) tyr) hr diarrhea distension pain energy loss ulceration glossia clubbing

1. 34 5 5

2. 27 25 7

3. 34 8 5

4. 35 0.75 6

5. 31 0.5 4

6. 47 20 10

7. 24 0.75 8

8. 36 0.5 6

9. 43 8 4

+ +

+ +

+ +

+ +

+ +


+ +


+ +

+ + - +

+ - +

+ + + -

+ - +

+ - + +

+ + - - -

+ + + -

+ + + + +

+ - -


Six of the 9 responders showed slight coarsening of the jejunal mucosa with minima1 dilatation of the smal1 in- testine on barium studies. Al1 had normal barium enema examinations.



JejunaJ Biopsy

Morphology before gluten-free diet. Al1 17 pa- had a peroral jejunal biopsy, using a multiple biopsy capsule4 which obtains at least three separate pieces of jejunum. Of the 9 responders, 2 had jejutial biopsies taken on only one occasion, 6 on two sepa- rate occasions and one on four separate occasions, making 54 pieces of jejunum available for study. Dis- setting microscopic examination of the jejunal sur- face in each case was essentially normal with no evidente of convolutions, or flat mosaic pattern. His- tologic examination revealed a normal villous ap- pearance, but with increased cellular infiltraticin of the lamina propria and the epithelium. Cel1 count- ing” was done on biopsies from al1 17 patients and 17 normal control subjects by one person (B.T. Cooper) who was unaware from which gr8up the specimens

Tabie 2. Laboratory Data at Presentation

were obtained. There was a significant increase in the plasma cells of the lamina propria (P < 0.001) and epithelial lymphocytes (P < 0.005) and a signifi- cant fa11 in the lymphocytes of the lamina propria (P

< 0.025) in the 9 responders as compared with the 8 nonresponders and the 17 control subjects (Table 3).

None had an increased eosinophil count in the la- mina propria.

Brush-border enzymes. The enzyme levels of lactase and maltase’ from 5 responders were within normal levels.

]ejunaJ aspirate bacteriology. In al1 17 pa- tients, the initial aspirate was immediately sent for bacterial viable count which did not exceed 104 or- ganisms/ml of mixed types of gram-positive aer- obes.

Period of Observation Before Gluten-free Diet Al1 patients were followed regularly from 6 mo-7 yr (mean 31 mo) before a gluten-free diet was started (Table 4). Antidiarrhetil agents, anti- spasmodics, bran, or other bulk-forming agents failed to provide any symptomatic relief. A milk-free diet was given to each responder for at least 4 mo without benefit in 5 and with only minor improve- ment in abdominal discomfort and distension, but


No. (g%) (m")

1. 14.0 80

2. 13.9 87

3. 13.2 81

4. 13.7 90

5. 13.1 97

6. 14.7 87

7. 13.7 94

8. 14.3 89

9. 13.1 85

Folate (pg/ml)

~- 6.3 1.2 4.8 2.4 3.2 4.4 9.0 2.0 10.6

Albumin Alk. phos. Iron Seromucoids W IgA IgM Fecal fat

(g%) (KAU) (mg%) (mg%) tw5) (mg%) (mg%ó) (g/24 hr) HLA-B8

50 7 112

45 9 151

40 3 123

48 11 67

39 6 190

42 7 84

48 5 62

43 7 207

46 5 76

102 1920 1140

80 1550 240

96 920 156

102 - -

- 1ooO 45

- 90 90 90

- -

1320 228

1600 252

1000 210

86 200 32 -

92 - 200

96 85

0.8 -

1.8 +


4.2 +

- -

- -

3.9 -

1.9 +

5.0 -



Table 3. jejunal Biopsy Ce11 Counts


Lamina Propria

Epithelium Lymphocytes Plasma cells (per mmz) Lymphocytes (per mm’) (per mm length)

Mean SE Mean SE Mean SE

A. Mean Cel1 Counts with Standard Errors of the Mean

Controls 17 1544 98 2982 159 50 4

Responders (ND) 9 2987 188 2227 147 82 6

Responders (GFD) 8 1755 112 3178 280 54 4

Nonresponders (ND) 8 1887 217 3055 275 53 7

Nonresponders (GFD) 4 1700 347 3550 400 47 5

Lamina propria

Unpaired groups

Plasma cells

t P

Lymphocytes Epithelium Lymphocytes

t P t P

B. Stotistical Analysis of CelJ Counts Using Unpaired t-Test

Controls vs. Responders (ND) vs. Responders (CFD) vs. Nonresponders (ND)

5.04 <O.OOl 2.40 <0.025 3.2 CO.005

1.00 NS 0.49 NS 0.50 NS

1.09 NS 0.21 NS 0.27 NS

Responders (ND)

vs. Responders (GFD) VS Nonresponders (ND)

4.10 <O.OOl 2.23 CO.05 2.80 0.02

2.72 0.02 1.96 NS 2.23 0.05

ND = Normal diet. GFD = Gluten-free diet.

without effect on the diarrhea in 4. The non- responders derived no benefit from this treatment.

Clinical Response to Gluten-j’ree Diet

A recurring feature in the histories of these patients was exacerbation of symptoms by the in- gestion of bread. Therefore, in view of our singular lack of success in treating these subjects, a 3-mo trial of a gluten-free diet was instituted. In 9 patients the response to the gluten-free diet was dramatic, for within 2 wk each patient noted an improvement in

the frequency and consistency of their stools and a lessening of their abdominal symptoms. Al1 9 be- came wel1 with 1-2 stools/day. Wcturnal diarrhea, abdominal pain, and other intestinal symptoms dis- appeared. Al1 of the patients commented on an in- creased feeling of wel1 being, and some remarked that their associates had noted an improvement in their temperament. These 9 patients have now been on a gluten-free diet for periods varying between 4 and 6 yr (Table 4).

The remaining 8 patients either derived no benefit whatsoever from a gluten-free diet (5 patients) or

Tabje 4. Duration of Fellow-up on Normal Diet and on Gluten-free Diet Before 30 g Gluten Challenge and the Double- Blind Challenge Together with Symptoms After 30 g Gluten

Patient No.


Normal diet.


F.U. GFD at gluten





Symptoms after gluten 30 g Abd.

Distension Diarrhea Malaise

F.U. GFD before double-blind


1 7 9 + + + 50

2 0.5 5 + + + + 46”

3 1 24 + + + + 60

4 4.25 NO challenge 44”

5 0.5 12 + + + 50

6 2 4 + + + + 42”

7 4.25 7 + + - + 42

8 3.25 9 + + + + 40

9 0.75 5 + + + + 38

F.U. = Follow-up. GFD = Gluten-free diet. Abd = Abdominal. 0 Time on gluten-free diet but not in double-blind challenge.


had experienced only a transient improvement (3 patients). Al1 8 returned to a normal gluten-contain- ing diet without alteration in their symptoms. NO other exclusion diets have been tried.

lejunal Biopsy Findings on Gluten-free Diet Four nonresponders and 8 responders were rebiopsied immediately before gluten challenge, while on a gluten-free diet for periods varying from

4 to 24 mo (mean 9 mo). The remaining responder had developed ischemic heart disease and was not submitted to repeat jejunal biopsy, or gluten chal- lenge.

The jejunal mucosal cel1 counts of the 4 non- responders showed no change. By contrast, exami- nation of the 24 biopsy specimens from the 8 re- sponders showed significantly less cellular infiltration of the lamina propria and epithelium (Table 3) than before the diet and not significantly different from those of normal controls.

Gluten Challenge

Clinical responses. (a) Eight responders whilst on gluten-free diet were admitted to the Unit and challenged with a single dose of 30 g gluten im- mediately after repeat jejunal biopsy (Table 4). Four of the nonresponders were similarly challenged. Al1 8 responders suffered abdominal distension, dis- comfort, and excessive rumbling within 8-12 hr after ingestion of gluten. Five developed diarrhea and al1 8 felt unwell and excessively tired for up to 1 wk after

the challenge. NO effects were experienced by the 4 nonresponders.

(b) After periods varying between 2 and 3 yr on a gluten-free diet, 5 patients (cases 1, 2, 5, 6, and 9) agreed to further challenge with a substance un- known to them. Sachets containing 20 g of gluten were incorporated into a gluten-free commercially available tomato soup and taken daily for 1 wk. The response was assessed by an independent doctor who had no knowledge of what had been adminis- tered. Four patients had relatively severe reactions with abdominal pain and discomfort, malaise and diarrhea (nocturnal diarrhea in 1 case) coming on within 24 hr, the symptoms persisting for the whole week. The 5th patient experienced only repeated bouts of flatulence.

At the end of the trial, 1 U was allotted for each symptom ( 2 if moderately severe, 3 if severe) experi- enced each day and single units for each bowel ac- tion and for the occurrence of diarrhea, or nocturnal bowel action. The sum total of units for each week was thus determined and, on breaking the code, the percentage change in symptoms between the control weeks and the weeks of sachet administration could be calculated. For each patient the symptoms pro- duced during the week of gluten administration were more than those in the other weeks. Using Stu- dent’s paired t-test, the percentage changes in symp- toms were significantly greater in the week of gluten administration than either the control week (df5, t = 3.84, P < 0.01) or the gluten-free sachet week (df5, t

= 5.36, P < 0.0025), and there was no differente be- tween the gluten-free week and its control (df5, t = 1.29, P < 0.15).

These differences were underlined by the occur- rente of centra1 abdominal pain (cases 1, 7, and 8), severe headache, also sore mouth, and lips (cases 8 and 9) during the gluten week, but not in the other weeks. Case 8, moreover, was unable to complete her sachets on the 3rd day owing to the severity of symptoms, though she had experienced none during the gluten-free week. Case 3 had only minima1 dis- turbance with abdominal distension and flatulence during the gluten week and was asymptomatic in the other 3 wk.

(c) Three patients received an “inadvertent blind Jejunal biopsy responses. Seven of the 8 re- challenge.” Cases 3 and 8 had severe abdominal sponders challenged with 30 g gluten had further je- pain, diarrhea, and malaise for 4-6 days after the in- junal biopsies 24 hr after gluten ingestion. In all, gestion of a fruit flavored yogurt normally taken more than 21 specimens of jejunal mucosa were ex- without upset. Case 7 had similar severe symptoms amined. There were no histologie changes except in after ingesting a particular sauce previously in- the lamina propria cel1 counts between the pre- and nocuous. Inquiry of the food manufacturers revealed postchallenge biopsies. There was a rise in lamina that gluten-containing flour had recently been incor- porated into these products.

(d) A double-blind crossover trial was undertaken on 6 patients who had taken a gluten-free diet for an average of 46 mo (cases 1, 3, 5, 7, 8, and 9). Sachets containing 1 g of either (a) gluten-free fleur, or (b) gluten were prepared, coded, and distributed by the Pharmacy staff, who took no other part in the trial.

The patients were instructed to complete a proforma each day, recording symptoms of malaise, nausea, vomiting, flatulence, and distension as absent, mild, moderate, or severe, together with the number of bowel actions, presence of diarrhea, and nocturnal bowel movement. In addition, any other symptoms not listed were to be noted. This record was to be continued for 4 wk. The patients were instructed to swallow 20 sachets randomly through each day for the first 3 days of weeks 2 and 4. The patients con- tinued to take their gluten-free diet throughout this period.



propria plasma cells in 6 of the 7 responders after gluten (df 6, mean rise 297 SE 118 cells/mm2, t = 2.52, P < 0.05) and a significant fa11 in lamina propria lymphocytes (df 6, mean fa11 1168 SE 175 cells/mm’, t = 6.67, P < 0.001). There were no changes in epithe- lial lymphocyte counts or in lamina propria eosino- phil counts. NO changes were found in any of the cel1 counts after challenge in the biopsies of the 4 nonresponders.

ImmunoIogicaI changes. (a) Complement components. NO change in Clq, C3, C4, C6, or C7 levels were detected’ over 24 hr after 30 g gluten challenge in the plasma of the 7 responders. NO com- plement breakdown products were found in the plasma by immunoelectrophoresis using specific anti-3d antiserum (Netherlands Red Cross Blood Transfusion Service).

(b) Antigluten antibodies were not detected” in the serum of 4 responders 24 hr after gluten challenge.

(c) Anticonnective tissue antibodies? IgA or IgG class antibodies were not present in the serum either before, or 24 hr after gluten challenge in the 7 re- sponders tested. Neither were they detected in the jejunal juice of two responders either before, or 24 hr after gluten challenge, but were not checked in the nonresponders.

(d) There were no differences in the levels of serum IgE in the 7 responders tested before, or 24 hr after gluten challenge. The peripheral blood eosino- phil counts in the 4 responders studied did not alter after challenge.


These patients form a relatively uncommon group in the experience of a Unit which sees many hundreds of patients with disorders of the smal1 and large intestine each year. The evidente that they are gluten sensitive is both clinical and morphologic.

The “dramatic clinical response” to a gluten-free diet has persisted for an average of nearly 5 yr after many months or years of incapacitating diarrhea.

Furthermore, symptoms returned on forma1 chal- lenge with gluten, after conscious lapse in diet, or more significantly in 3 patients after unwittingly in- gesting foods containing gluten due to recent change in manufacture. Secondly, there were minor, but sig- nificant abnormalities in the jejunal mucosal cel1 counts on a gluten-containing diet, a return of the counts to normal on a gluten-free diet and signifi- cant changes in these counts after gluten challenge.

By contrast, in those patients with chronic diarrhea who failed to respond to a gluten-free diet, the cel1 counts were within normal limits even after chal- lenge. The possibility that such jejunal cel1 changes

after gluten challenge may occur in normal subjects on a gluten-free diet has only been checked in 4 of the origina18 unresponsive patients. None of these 4 developed symptoms or had significant change in the cel1 counts. The possibility of placebo response to dietary treatment or a subjective response to glu- ten challenge always needs consideration in adult patients. Prolonged follow-up has minimized this possibility for relapse might have been expected in some patients during this period, were the response due to a placebo effect.

It seems unlikely that the patients with gluten in- tolerante have celiac disease for several reasons.

The absente of areas of flat jejunal mucosa in any patient after a number of multiple biopsies on sepa- rate occasions should exclude the diagnosis of celiac disease, for it is improbable that such areas were missed since the average size of the specimens are considerably larger than those obtained by the Crosby capsule. Normal brush-border disacchari- dase levels also make the diagnosis of celiac disease unlikely,‘” while in patients previously on a strict gluten-free diet, lactase levels fa11 as early as 1 hr af- ter gluten challenge.” Even though each patient in this series had a normal gluten intake at the time of the original jejunal biopsy, their initial jejunal cel1 counts were similar to those found in celiac patients on a gluten-free diet rather than in celiacs on a nor- mal diet.’ Jejunal response 24 hr after gluten chal- lenge was different from that described in celiac dis- ease.l’ Other evidente against celiac disease is the paucity of abnormal laboratory values, the absente in any patient of a childhood or family history sug- gestive of celiac disease, the normal incidence of HL-A BB in the series, and the absente of gluten antibodies or of complement changes in the serum.

Whether the fact that al1 patients are female is sig- nificant cannot yet be determined.

Immunologie abnormalities have not been demon- strated apart from minor, but significant changes in plasma cel1 and lymphocyte counts in the jejunal mucosa. The absente of such changes mitigates against immunologie disturbances being responsible for this condition. At present, the mechanism of the production of symptoms by gluten in these patients must remain a matter for conjecture. It is important that such patients are not regarded as having celiac disease, but their existente makes the definition of celiac disease stil1 more difficult.


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